3-amino-1, 2-dihydro-3h-pyrido [3, 2, 1-kl]-phenothiazines



S-All/HNO-1,2-DlHYDRO-3H-PYRIDO [3,2,1-KL1-PHENOTHIAZINES Paul N. Craig,Roslyn, and John J. Lafierty, Levittown, Pa., assignors to Smith, Kline& French Laboratories, Philadelphia, Pa, a corporation of PennsylvaniaNo Drawing. Application December 5, 1957 Serial No. 700,757

8 (Ilaims. (Cl. 260-243) phenothiazines of this invention arerepresented by the following structural formula:

Formula 1 s 9 R" t I "Y 10 12 4 when:

R represents hydrogen, chlorine, bromine, fluorine or trifluoromethyl,preferably in the l0-position,

Y represents hydrogen, lower alkoxy advantageously methoxy, lower alkyladvantageously methyl, preferably in the 4-position; and

Z represents amino, lower alkylarnino, di(lower alkyl) amino,pyrrolidinyl, piperidinyl, (N-lower alkyl)pipera- Zinyl, morpholinyl orthiomorpholinyl.

Advantageous compounds of this invention are represented by thefollowing structural formula:

Formula 2 when:

R represents chlorine, bromine, fluorine or trifluoromethyl; and

Z represents amino, di(lower alkyl) amino, pyrrolidinyl or (N-loweralkyl)piperazinyl.

By the term lower alkyl where used herein alone or in combination withother terms, alkyl groups having not more than 6 carbon atoms,preferably not more than 4, are indicated.

This invention also includes pharmaceutically acceptable salts of theabove defined bases formed with nontoxic organic and inorganic acids.Such salts are easily prepared by methods known to the art. The base isreacted with either the calculated amount of organic or inorganic acidin aqueous miscible solvent, such as ace- United States Patent 02,919,271 Patented Dec. 29, 1959 tone or ethanol, with isolation of thesalt by concentration and cooling or an excess of the acid in aqueousimmiscible solvent, such as ethyl ether or chloroform, with the desiredsalt separating directly. Exemplary of such organic salts are those withmaleic, fumaric, benzoic, ascorbic, pamoic, succinic,bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicyclic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palrnitic, itaconic,glycolic, p-aminobenzoic, glutamic, benzenesulfonic andtheophyllineacetic acids as well as with the S-halotheophyllines, forexample, 8-chlorotheophylline and 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric and nitric acids. Of course, these salts may alsobe prepared by the classical method of double decomposition ofappropriate salts which is well-known to the art.

The compounds of this invention are prepared from substituted 2,3-dihydro-3-keto-1H-pyrido [3,2, l-kl] phenothiazines which are in turnprepared by cyclizing the corresponding 10 (2 carboxyethyl)phenothiazine's. Starting with the substituted phenothiazine nucleus,the following synthetic route shows the preparation of the 2,3-dihydro-3-ket0- lH-pyrido 3,2, l -kl] phenothiazine intermediates.

R Y R Y III N OHZCH2000H The terms R and Y are as previously defined.

The phenothiazine starting material unsubstituted in the 10-position isconverted to the l0-(2'-cyanoethyl)- phenothiazine by reacting thelfl-unsubstituted phenothiazine either with a large excess ofacrylonitrile or with about a molar equivalent of acrylonitrile in aninert solvent such as benzene or ether, preferably in the presence of acatalytic amount of strong base, such as a quaternary base, forinstance, benzyltrimethylammonium hydroxide. The resulting10-(2-cyanoethyl)-phenothiazine is hydrolyzed to the correspondingl0-(2'-carboalkoxyethyl)-analogue by reacting a solution of the cyanocompound in an inert solvent such as dioxane with a suitable acid, forinstance, hydrogen chloride in methanol. Addition of water andsubsequent hydrolysis of the l0-(2'-carboalkoxyethyl)-phenothiazine byrefluxing in a lower alcohol such as methanol or ethanol with an alkalimetal hydroxide, for example, potassium hydroxide or sodium hydroxidefollowed by acidification produces the desired 10- (2'-carboxyethyl)-phenothiazine.

Alternatively, the 10-(2-cyanoethyl)phenothiazine is hydrolyzed withaqueous alcoholic alkali metal hydroxide solution followed by subsequentacidification.

The l0-(2-carboxyethyl)phenothiazine is cyclized by refluxing with adehydrating agent such as phosphorus pentoxide or, preferably,triiiuoroacetic anhydride in an inert non-polar solvent which is nothydroxylated such as ether, toluene or benzene to form2,3-dihydro-3-keto-1H- pyrido [3 ,2, l -kl] phenothiazine.

The 3-amino-1,2-dihydro 3H pyrido[3,2,1-kl]phenothiazine compounds ofthis invention are prepared according to the following synthetic route:

n I I when: R and Y are as previously described.

The oxime derivative of the cyclic ketone is prepared preferably byreacting the ketone with hydroxylamine hydrochloride in a suitabletertiary organic base such as pyridine or collidine for short periods oftime, for in stance, from about one to six hours at reflux temperature.

Reduction of the oxime to the 3-amino-1,2-dihydro-3H-pyrido[3,2,1-kllphenothiazine is accomplished either by chemicalreduction or catalytic hydrogenation. With respect to the preferredchemical reduction the oxime in an organic solvent preferably a loweralcohol such as ethanol or methanol is reacted with the reducing agent,for example, sodium amalgam and glacial acetic acid at room'temperaturefor a short period of time, for instance, from 30 to 90 min. The3-amino-1,2-dihydro-3H-pyrido- [3,2,lkl]-phenothiazine is convenientlyseparated from the reaction mixture in the form of its hydrochloridesalt. Other reducing agents such as zinc or stannous chloride inhydrochloric acid may be used.

' Where catalytic hydrogenation is employed, the oxirne in an organicsolvent, for example, a lower alcohol, such as ethanol or methanol isreduced using a catalyst, for example, platinum oxide, at about 75-l25C. and about 400600 p.s.i. for several days. Other catalysts which maybe used are, for example, Raney nickel or palladiumon-charcoal.

. The thus formed 3-amino-1,2dihydro-3H-pyrido[3,2,lkllphenothiazinesare alkylated by reaction With a reactive alkyl ester or by reductivealkylation to form the 3-substituted amino compounds of Formula 1. Forthe alkylation, any reactive alkyl ester containing the desired moietymay be used, such as the preferred halides, for example iodide, bromideor chloride. The condensation is carried out advantageously by refluxingthe reactants in an inert aromatic solvent such as, preferably benzene,

toluene or xylene, in which at least one of the reactants must besoluble. A suitable acid-binding agent is usually included, such as analkali metal cabonate, bicarbonate, hydroxide, amide or hydride,preferably the sodium or potassium compounds.

Advantageously, the heterocyclic amine derivatives are prepared bycarrying out the reaction on the primary amine with a reactivedifunctional alkyl ester such as, for example, by reacting the primaryamine with 1,4-dibromobutane to form the pyrrolidinyl compound.

Alternatively, the 3-amino-1,2-dihydro-3H-pyrido-[3,2,l-kllphenothiazines are reacted with a suitable keto or aldehydocompound under reductive conditions such as with formaldehyde-formicacid or in a hydrogen atmosphere with a catalyst such as Raney nickel,palladinized charcoal or platinum oxide.

Advantageously, 3 dimethylamino 1,2 dihydro-3H-pyrido[3,2,1-kllphenothiazines may be prepared by this method, i.e.reductive alkylation. An aqueous solution of the primary amine orpreferably a mineral acid salt such as the hydrochloride is madealkaline with a basic solution such as 10% sodium hydroxide, then acidwith formic acid solution. The mixture is refluxed with aqueousformaldehyde such as a 37% solution for about two hours, filtered, madealkaline and extracted with benzene. Concentration of the benzenesolution gives the l,2-dihydro-3 -dimethylamino-3H-pyrido 3 ,2, l-kl]phenothiazine.

It will be apparent to one skilled in the art that the novel compoundsof this invention may exist in various isomeric forms since they possessa ring carbon atom asymmetrically substituted. The scope of thisinvention includes the separated isomers as Well as mixtures thereof.The preferred compounds of this invention are the mixtures of isomersproduced as described hereafter.

The following examples are not limiting but are illustrative ofcompounds of this invention and the procedures for their preparation andwill serve to make fully apparent all of the compounds embraced by thegeneral formula given above and the preparation thereof respectively.

Example 1 A solution of 16.0 g. of10-(2-cyanoethyl)-2-t1i-fluoromethylphenothiazine in 250 ml. of drydioxane is mixed with a solution of 31.0 g. of hydrogen chloride in ml.of dry methanol. After standing at room temperature for 24 hours, 6 ml.of water is added. About half of the solvent is removed in vacuo. Aprecipitate of ammonium chloride is separated by filtration. Thevolatiles are completely removed in vacuo and the gummy residue vacuumdistilled to give l0-(2-carbomethoxyethyl)2-trifluoromethylphenothiazine, BR 172 to 175 C. at 55 microns.

A solution of 1.0 g. of this ester in 100 ml. of methanol containing oneequivalent of potassium hydroxide with 10 ml. of water is heated atreflux for two hours. The solution is concentrated to give a residuewhich is washed with water and acid, then taken up in benzene. Thebenzene solution is extracted with dilute sodium hydroxide. The extractsare neutralized to yield crystals of10-(2'-carboxyethyl)-2-trifiuoromethylphenothiazine, M.P. -180181C.

A solution of 7.5 g. of this acid in 300 ml. of dry benzene with 40 m1.of trifiuoroacetic anhydride is heated at reflux for three hours. Thesolution is evaporated after washing with dilute sodium hydroxide togive crystals of the cyclic ketone, M.P. 158-159 C.

A solution of 2.5 g. of the ketone and 1.38 g. of hydroxylaminehydrochloride in 80 ml. of pyridine is heated at reflux for two hours.After evaporation of the volatiles, the residue is taken up in benzene.Concentration and cooling gives yellow crystals of the desired oxime,M.P. 202-203 C.

A solution of 1.6 g. of the oxime in 70 ml. of ethanol is stirred while23.7 g. of sodium amalgam and 1.5 ml. of glacial acetic acid are addedportionwise. After the reaction mixture is stirred for about one hour, amixture of 150 ml. of water and 100 ml. of ether is added. The resultingreaction mixture is treated with dilute hydrochloric acid to form thehydrochloride salt of 3-amino-1,2-dihydro-10-trifluoromethyl-3H-pyrido[3,2,1-kl]phenothiazine ascrystals from ethanol-ether, M.P. 254-255 C.

Example 2 A slurry of 12.1 g. of the primary amine from Example 1 in 500ml. of water is made alkaline with 10% sodium hydroxide solution, thenacid with formic acid solution. Aqueous 37% formaldehyde (60 ml.) isadded and the resulting mixture heated on the steam bath for two hours.The filtered mixture is made alkaline with 10% sodium hydroxide.Extraction with benzene gives an oily residue upon concentration;l,2-dihydro-3-dimethylamino-10-trifluoromethyl-3 H-pyrido 3 ,2, l-kl]phenothiazine.

This oil is dissolved in ether and treated with alcoholic hydrogenchloride to separate the crystalline hydrochloride, M.P. 239240 C. a

Example 3 Example 4 A solution of 2.86 g. ofl-(2'-carboxyethyl)-phenothiazine in 75 ml. of benzene with 2.1 g. oftrifluoroacetic anhydride is heated for a few minutes and poured into anexcess of water. After separation of the organic layer, the desiredcyclic ketone (2,3-dihydro-3-keto-1H-pyrido- [3,2,1-kllphenothiazine) isrecovered by drying, washing and evaporating the benzene layer, M.P.102104 C.

A solution of 5.15 g. of the ketone is reacted with 2.82 g. ofhydroxylamine hydrochloride in 100 ml. of pyridine and 20 ml. ofethanol. The reaction is worked up as in Example 1 to give thecorresponding oxime as crystals, MP. ZZZ-224 C.

A slurry of 11.0 g. of oxime in 50 ml. of ethanol is hydrogenated withplatinum oxide (0.4 g.) at 95-100 C. and about 500 p.s.i. for six days.The mixture is filtered to give the crude product which is extractedsuccessively with acetic acid and ethanol. The combined filtrates areconcentrated and diluted with water. The resulting solid is thendissolved in ethanol and treated with hydrogen .chloride gas to givecrystals of 3-amino-l,2-dihydro-3H- pyridol3,2,l-kllphenothiazinehydrochloride, M.P. 243- 248 'C.

Example 5 A slurry of 6.5 g. of the hydrochloride of Example 4 in 100ml. of water is made alkaline with sodium hydroxide, then formic acid isadded until a clear solution results. An excess of formalin is added.After heating on the steam bath for two hours, the reaction mixture isextracted with benzene. The extracts are evaporated and the residuetaken up in ethyl acetate. An excess of maleic acid solution is added toseparate the maleate salt of 1,2-dihydro-3-dimethylamino-3H'pyrido [3,2,1-kl] phenothiazine, M.P. 198-199" C.

' Example 6 A mixture of 17.4 g. of3-amino-1,2-dihydro-10-trifluoromethyl 3H pyridol3,2,1-k11phenothiazinehydrochloride (prepared as in Example 1) in 500 ml. of water is madealkaline with 10% sodium hydroxide solution. The free amine is extractedwith benzene.

The benzene extracts together with 6.8 g. of n-butyl bromide and 5.0 g.sodium carbonate are heated at reflux for ten hours. The cooled reactionmixture is treated with water and the organic layer is separated. Uponevaporation of the solvent in vacuo, the crude product, 3-n-butylamino-l ,2-dihydro 10-trifluoromethyl-3H-pyrido-[3,2,1-kl1phenothiazine, is obtained. The product is purified bymolecular distillation at 180 C. and 10 microns.

Example 7 A mixture of 14.4 g. of the3-amino-l0-ch1oro-1,2-dihydro-3H-pyrido[3,2,1-kl1phenothiazine, preparedas in Example 3, 7.5 g. of n-hexyl bromideand 4.0 g. of potassiumcarbonate in 300 ml. of benzene is heated at reflux for 12 hours. Thecooled reaction mixture is poured into water and the organic layer isseparated. Upon removal of the dried solvent in vacuo the crude product,10-chloro- 1,Z-dihydro-3-n-hexylamino-3H-pyrido [3,2,1-kl]phenothiazine, is obtained. Y

-6 Example 8 A mixture of 14.4 g. of 3-amino-10-chloro-1,2-dihydro-3H-pyrido[3,2,1-kl1phenothiazine, prepared as in Example 3, in formicacid solution with 5 .0 g. of aqueous 37% formaldehyde is heated on thesteam bath for three hours. The filtered mixture is made alkaline with10% potassium hydroxide. Extraction with benzene and evaporation of thesolvent in vacuo yields the product, l0-chloro-1,2-dihydro-3-dimethylamino-3H-pyrido [3 ,2,1-kl]phenothiazine..

The product (1.0 g.) is dissolved in 250 ml. of ether and treated withan excess of alcoholic hydrogen bromide to separate the crystallinemonohydrobromide.

Example 9 A mixture of 17.4 g. of 3-amino-1,2-dihydro-10-trifluoromethyl3H pyrido[3,2,1-k11phenothiazine hydrochloride (prepared as inExample 1) in 500 ml. of Water is made alkaline with 10% sodiumhydroxide solution. The free amine is extracted with benzene. Thebenzene extracts together with 10.8 g. 1,4-dibromobutane and 10.0 g.sodium carbonate are heated at reflux for ten hours. The cooled reactionmixture is poured into water and the benzene layer separated. Uponevaporation of the solvent in vacuo the product1,2-dihydro-3-(1-pyrrolidinyl)- 10trifluoromethyl-3H-pyrido[3,2,l-kllphenothiazine, 'is obtained.

The product (1.0 g.) is dissolved in 250 ml: of'ether and treated withan excess of alcoholic hydrogen-chloride to separate the crystallinemonohydrochloride.

Example 10 A mixture of 16.1 g. of-3-amino-1,2-dihydro-10-trifluoromethyl-3H-pyrido [3,2,l-kl]phenothiazine hydrochloride (prepared as in Example 1) in 300 ml. ofwater is made alkaline with 10% potassium hydroxide solution. The freeamine is extracted with xylene. g

The xylene extracts together with 11.5 g. of 1,5-dibromopentane and 14.0g. of potassium carbonate are heated at reflux for 14 hours. The cooledreaction mixture is treated with water and the xylene layer isseparated. Evaporation of the solvent in vacuo yields the crude product,1,2-dihydro-3 1-piperidinyl)10-trifluorornethyl-3H-pyrido[3,2,l-kllphenothiazine which is purifiedby molecular distillation at 200 C. and 10 microns.

A solution of the free base (500 mg.) in ml. of ether is reacted with anexcess of glacial acetic acid to yield the monoacetate salt.

Example 11 I fluoromethyl-3H-pyrido [3,2,1 kl] phenothiazinehydrochloride (prepared as in Example 1) in 300 ml. of water is madealkaline with 10% sodiumhydroxide solution. The free amine is extractedwith toluene.

The toluene extracts together with 7.8 g. of methylbis(B-chloroethyl)amineand 25.0 g. of tributylarnine are heated atreflux for ten hours. cooled, then poured into water. The organic layeris separated. Evaporation of the solvent in vacuo yields the crudeproduct 1,2-dihydro-3-(4-methyl-1-piperazinyl) -l0-trifluoromethyl-3H-pyrido 3 ,2, l-kl] phenothiazine.

A Solution of this product (1.0 g.) in 100 ml. of ethanol is treatedwith hydrogen chloride gas to give crystals of the dihydrochloride salt.

Example 12 The reaction mixture is 7 the crude product,1,2-dihydrb-3-(4-morpholinyl)-10- trifluoromethyl-3 H-pyri do [3 ,2,l-kl] phenothiazine.

Example 13 u A mixture of 14.4 g. of S-amino-chloro-l,2-dihydro-SH-pyrido[3,2,1-kllphenothiazine (prepared as in Example 3) 7.9 g. ofbis(B-chloroethyl)sulfide and 10.0 g. of sodium carbonate is heated atreflux for ten hours. The cooled reaction mixture is poured into waterand the organic layer is separated. Upon evaporation of the solvent invacuo, the crude product, 10-chloro-1,2-dihydro 3 (4 thiomorpholinyl) 3Hpyrido[3,2,lkllphenothiazine, is obtained.

. Example 14 A solution of 10.8 g. of l-chlorophenothiazine in 500 m1.of acrylonitrile and 1 ml. of a 40% solution of benzyltrimethylammoniumhydroxide is heated on a steam bath for two hours. After cooling, thecrystalline product, 10-(2-cyanoethyl)-1-chlorophenothiazine, isfiltered ofi and is recrystallized from acetone.

The cyano compound (10.0 g.) is hydrolyzed to the corresponding10-(2'-carbomethoxyethyl) compound by reaction with hydrogen chloride(30 g.) in 150 ml. of dry methanol. Hydrolysis of this ester (3.0 g.) byrefluxing in methanol with one equivalent of potassium hydroxide yields10-(2-carboxyethyl)-1-chlorophenothiazine. A solution of 6.0 g. of thisacid in 250 ml. of dry benzene with 40 ml. of trifluoroacetic anhydrideis heated at reflux for three hours. Washing with dilute sodiumhydroxide and evaporating the solution yields 11- chloro 2,3 dihydro 3keto 1H pyrido[3,2,l-kl] phenothiazine. This ketone (1.0 g.) is reactedwith hydroxylamine hydrochloride (0.6 g.) by heating in 50 ml. ofpyridine and the resulting oxirne is reacted with sodium amalgam (20.0g.) in 75 ml. of ethanol and 1.5 ml. of

glacial acetic acid and isolated as in Example 1 to give 3 amino 1,2dihydro 11 chloro 3H pyrido[3,2,1- kllphenothiazine hydrochloride.

A mixture of the hydrochloride in. 500 ml. of water is made alkalinewith 10% sodium hydroxide solution. The 3amino-1,2-dihydro-11-chloro-3H-pyrido[3,2,1-kl] phenothiazine isextracted with xylene.

The xylene extracts, 9.8 g. of butyl bis(,B-chloroethyl) amine and 14.0g. of potassium carbonate are heated at reflux for ten hours. The cooledreaction mixture is poured into water and the organic layer isseparated. Upon evaporation of the solvent in vacuo, the product, 3 (4'butyl 1' piperazinyl) 1,2 dihydro 11-chloro-3H-pyrido[3,2,1-kl]-phenothiazine is obtained.

A Solution of 1.0 g. of the free base in 100 ml. of ether is treatedwith an excess of alcoholic hydrogen chloride solution to separate thecrystalline dihydro chloride.

Example 15 A mixture of 13.6 g. of 3-amino-1,2-dihydro-1l-chloro-3H-pyrido[3,2,1-kllphenothiazine hydrochloride, prepared as in Example14, in 500 ml. of water is made alkaline with 10% sodium hydroxidesolution, the acid with formic acid solution. Aqueous formaldehyde (90ml.) is added and the resulting mixture heated on the steam bath for twohours. The filtered mixture is made alkaline with 10% sodium hydroxidesolution. Extraction with benzene and concentration of the solutionyields 1,2-dihydro-3-dimethylamino-1l-chloro-3H-pyrido[3,2,1-kllphenothiazine.

An ether solution of 1.0 g. of the free base is treated with an excessof alcoholic hydrogen chloride to separate the crystallinemonohydrochloride.

3.0 g. of acrylonitrile and 0.5 g. of tributylamine in 400 ml. of etheris heated on a'stearnbath for four hours. Evaporation of the solvent andrecrystallization of the with formic acid solution.

residue from acetone yields the crystalline product, 10- 2'-cyanoethyl-3 -trifluoromethylphenothiaziue.

A solution of 8.0 g. of the cyano compound in 300 ml. of dioxane isheated on the steam bath with an aqueous methanol solution of sodiumhydroxide for two hours. The solution is concentrated to give a residuewhich is washed with water and with dilute hydrochloric acid.

The residue is then taken up with benzene. The benzene solution isextracted with dilute sodium hydroxide and the extracts neutralized toyield crystals of 10-(2- carboxyethyl) -3 -trifluoromethylphenothiazine.

A solution of 6.7 g. of this acid in 250 ml. of dry ether with 2.0 g. ofphosphorous pentoxide is heated at reflux for four hours. The solutionis concentrated to yield the crude product,2,3-dihydro-3-keto-9-trifluoromethyllH-pyrido[3,2,1kllphenothiazine.

A solution of 4.8 g. of the ketone and 2.8 g. of hydroxylaminehydrochloride in ml. of pyridine is heated at reflux for two hours. Thesolution is concentrated and the residue taken up in benzene.Evaporation of the solvent and cooling gives the yellow crystals of theoxirne.

The oxime (1.6 g.) is dissolved in ml. of ethanol; the resultingsolution is stirred while 23.7 g. of sodium amalgam and 1.5 ml. ofglacial acetic acid are added portionwise. After the reaction mixture isstirred for about one hour, a mixture of ml. of water and 100 ml. ofether is added. The resulting mixture is treated with dilutehydrochloric acid to form 3-amino-1,2-dihydro-9-trilluoromethyl- 3Hpyrido [3,2,1kl] phenothiazine hydrochloride as crystals fromethanol-ether.

A mixture of 17.4 g. of the hydrochloride in 400 ml. of water is madealkaline with 10% sodium hydroxide solution. The free amine is extractedwith xylene.

The xyleneextracts together with 12.3 g. of propyl bromide and 12.0 g.of sodium bicarbonate are heated at reflux for eight hours. The cooledreaction mixture is poured into water and the organic layer isseparated. Evaporation of the solvent in vacuo yields the crude product,1,2-dihydro-3-dipropylamino-9-trifiuoromethyl-3H-pyridoi3,2,l-kl]phenothiazine which is purified by moleculardistillation at 200 C. and 10 microns.

The product (1.0 g.) is dissolved in 150 ml. of ether and treated withan excess of alcoholic hydrogen chloride to separate the crystallinemonohydrochloride.

Example 17 A mixture of 17 .4 g. of3-amino-l,2-dihydro-9-trifluoromethyl-BH-pyrido [3,2, lkl] phenothiazinehydochloride (prepared as in Example 16) in 500 ml. of water is madealkaline with 10% sodium hydroxide solution, then acid Aqueous 37%formaldehyde (90 ml.) is added and the resulting mixture is heated onthe steam bath for two hours. The filtered mixture is made alkaline with10% sodium hydroxide solution. Extraction with benzene and evaporationof the solvent in vacuo yields1,2-dihydro-3-dimethylamino-9-trifiuoromethyl-3H-pyrido[3,2,1-kl1phenothiazinewhich is purifled by molecular distillation.

Example 18 1 4-trifiuoromethylphenothiazine (13.0 g.) is reacted with anexcess of acrylonitrile (500 ml.) under basic conditions as in Example14 to produce 10-(2'-cyanoethyl) -4-trifiuoromethylphenothiazine.

The cyano compound (16.0 g.) is hydrolyzed to the correspondingl0-(2-carbomethoxyethyl) compound by reaction with hydrogen chloride(31.0 g.) in 150 ml. of dry methanol. The ester is isolated and 1.0 g.is hydrolyzed by refluxing in 50 ml. of methanol with one equivalent ofpotassium hydroxide to yield10-(2-carboxyethyl)-4-trifluoromcthylphenothiazine. A solution of 7.5 g.of this acid in 300 ml. of dry benzene with 40 ml. of trifluoroaceticanhydride is heated at reflux for three hours. The volatiles areevaporated and the prodnot isolated as in Example 1 to give the2,3-dihydro-3- keto-8-trifluoromethyl-1H-pyrido [3 ,2, 1 -kl]phenothiazine. The ketone (2.5 g.) is reacted with hydroxylaminehydrochloride (1.38 g.) by heating at reflux in 100 ml. of pyridine. Theresulting oxime is reacted with 23.7 g. of sodium amalgam and 1.5 ml. ofglacial acetic acid in 75 ml. of ethanol with isolation as in Example 1to give 3-amino-1,Z-dihydro-8-trifluoromethyl-3H-pyrido[3,2,1kl]phenothiazine hydrochloride.

A slurry of 17.4 g. of the primary amine hydrochloride in 500 ml. ofWater is made alkaline with 10% sodium hydroxide solution, then acidwith formic acid solution. Aqueous 37% formaldehyde (90 ml.) is addedand the resulting mixture heated on the steam bath for two hours. Thefiltered mixture is made alkaline with 10% sodium hydroxide solution.Extraction with benzene and concentration of, the solvent yields theproduct, 1,2-dihydro-3-dirnethylamino-S-trifiuoromethyl-3H-pyrido 3 ,2,-

l-kllphenothiazine which is purified by molecular distillation at 180 C.and 10 microns.

A solution of 1.0 g. of the free base in ethyl acetate is added to asolution of mandelic acid in ethanol. Concentration of the resultingsolution and cooling yields the crystallinel,Z-dihydro-3-dimethylamino-8-trifluoromethyl-3H-pyrido 3 ,2,1-kl]phenothiazine mandelate.

Example 19 Z-Methylphenothiazine (10.6 g.) is reacted with an excess ofacrylonitrile (500 ml.) under basic conditions and isolated as inExample 14 to produce 10-(2'-cyanoethyl) -2-methylphenothiazine.

treated with an excess of hydrogen chloride to separate the crystallinehydrochloride.

Example 21 responding 10-(2-carbomethoxyethyl) compound by re- The cyanocompound (5.0 g.) is hydrolyzed to the corresponding10-(2-carbomethoxyethyl) compound by reaction with 15 g. of hydrogenchloride in 100 ml. of

dry methanol. Hydrolysis of this ester (1.0 g.) by refluxing in methanolwith one equivalent of potassium hydroxide yields 10 (2-carboxyethyl) 2methylphenothiazine. A solution of 6.0 g. of this acid in 250 ml. of drybenzene with 40 ml.. of trifluoroacetic anhydride is heated at refluxfor three hours. Washing with dilute sodium hydroxide and evaporatingthe solution yields 2,3-dihydro-3-keto-4 methyllH-pyrido[3,2,1-kl]phenothiazine. This ketone (1.0 g.) is reacted withhydroxylamine hydrochloride (0.6 g.) to give the corresponding oximewhich is then reacted with sodium amalgam (20.0 g.) and glacial aceticacid (1.5 ml.) and isolated as in Example 1 to give3-arnino-1,2-dihydro-4-methyl-3H-pyrido[3,2,1kllphenothiazinehydrochloride.

A mixture of 15.2 g. of the hydrochloride in 300 ml. of water is madealkaline with 10% aqueous sodium hydroxide solution. The free amine isextracted with benzene.

The benzene extracts together with 12.3 g. of hexylbis(,8-chloroethyl)amine and 14.0 g. of potassium carbonate are heatedat reflux for eight hours. The cooled reaction mixture is treated withwater and the benzene layer is separated. Upon evaporation of thesolvent in vacuo the product, 1,2-dihydro-3-(4-hexyl-l-piperazinyl) 4methyl 3H pyrido[3,2,1kllphenothiazine is obtained.

Example 20 .fied by molecular distillation at 180 C. and 10 microns.

The base (1.0 g'.) 'is dissolved in 200 ml. of ether and action with 15g. of hydrogen chloride in 100 ml. of dry methanol. Hydrolysis of thisester (1.0 g.) by refluxing in methanol with one equivalent of potassiumhydroxide yields 10 (2-carboxyethyl)-3 methylphenothiazine. A solutionof 6.0 g. of this acid in 250 ml. of dry benzene is heated at reflux forthree hours with 40 ml. of trifluoroacetic anhydride. Washing withdilute sodium hydroxide and evaporating the solution yields 2,3-dihydro-3-keto-5 -methyl-1I-I-pyrido 3,2, 1'-kl] phenothiazine. This ketone (1.0g.) is reacted with 0.6 g. of hydroxylamine hydrochloride to give thecorresponding oxime which is then reacted with 20.0 g. of sodium amalgamand 1.5 ml. of glacial acetic acid in 100 ml. of ethanol and isolated asin Example 1 to give 3-amino-1,Z-dihydro-S-methyl- 3H-pyrido[3,2,1-kl]phenothiazine hydrochloride.

A mixture of 15.2 g. of the hydrochloride in 500 ml. of Water is madealkaline with 10% aqueous sodium hydroxide solution. The free base isextracted with xylene.

The xylene extracts together with 13.7 g; of n-butyl bromide and 14.0 g.of potassium carbonate are heated at reflux for ten hours. The cooledreaction mixture is poured into water and the xylene layer is separated.Evaporation of the solvent in vacuo yields the product, 3 dibutylamino1,2-dihydro-5-methyl-3H-pyrido[3,2,1- kl] phenothiazine which ispurified by molecular distillation at 200 C. and 10 microns.

A solution of 1.0 g. of this base in 100 ml. of ethyl acetate is reactedwith an excess of maleic acid to give the maleate salt.

Example 22 A mixtureof 15.2 g. of 3-amino-1,2-dihydro-5-methyl- 3Hpyrido[3,2,1 kllphenothiazine hydrochloride (prepared as in Example 21)in 500 ml. of water is made alkaline with 10% sodium carbonate solution,then acid with formic acid solution. Aqueous 37% formaldehyde (90 m1. isadded and the resulting mixture heated on.

' lecular distillation at 190 and 10 microns.

kl]phenothiazine hydrochloride.

The free base (2.0 g.) is dissolved in 250 ml. of ether and treated withan excess of alcoholic hydrogen chloride to separate the crystallinehydrochloride.

Example 23 10 (2'-cyanoethyl)-2-methoxyphenothiazine, prepared by.reacting 2-methoxyphenothiazine (11.5 g.) with an excess ofacrylonitrile (500 ml.) under basic conditions followed by the isolationprocedure described in Example 14, is subjected to the following seriesof reactions with isolation procedures similar to those in Example 1 toproduce 3 amino 1,2-dihydro-4-methoxy-3H-pyrido[3,2,1-

The cyano compound (5.0 g.) is hydrolyzed with 15.0 g. of hydrogenchloride in ml. of dry methanol to give the corresponding10-(2-carbomethoxyethyl) compound. Hydrolysis of this ester (1.0 g.) byrefluxing in 50 ml. of methanol with one equivalent of potassiumhydroxide yields l0-(2-carboxyethyl)-2-methoxyphenothiazine. A solutionof 6.0 g. of this acid in 250 ml. of dry benzene is heated at reflux forthree hours with'40 m1.

of trifluoroacetic anhydride. Washing with dilute sodium hydroxide andevaporating the solution yields 2,3-dihydro3-keto-4-methoxy-lH-pyrido[3,2,l-kllphenothiazine. This ketone (1.5 g.)is reacted with (1.0 g.) of hydroxylamine hydrochloride by heating in 50ml. of pyridine to give the corresponding oxime which is then reactedwith sodium amalgam (20.0 g.) and glacial acetic acid (1.5 ml.) inethanol solution as in Example 1 to give 3 amino1,2-dihydro-4-methoxy-3H-pyrido[3,2,l-kl]- phenothiazine hydrochloride.

A mixture of the hydrochloride (16.0 g.) in 300 ml. of water is madealkaline with 10% sodium hydroxide solution. The free amine is extractedwith benzene.

The benzene extracts together with 7.8 g. of methylbis(p-chloroethyl)amine and 12.0 g. of sodium carbonate are heated atreflux for 12 hours. After cooling, the reaction mixture is treated withwater and the organic layer is separated. Evaporation of the solvent invacuo yields the product, 1,2-dihydro-4-methoxy-3-(4-methyl- 1-piperazinyl) -3H-pyrido [3,2,1-kllphenothiazine.

A solution of 3.6 g. of the base in ethyl acetate is treated with excesscitric acid. Concentration and cooling gives the dicitrate salt.

Example 24 3amino-1,2-dihydro-4-methoxy-3H-pyrido[3,2,1-kllphenothiazinehydrochloride (prepared as in Example 23) in'500 ml. of water is madealkaline: with 10% sodium hydroxide solution, then acid with formic acidsolution. Aqueous 37% formaldehyde (90 ml.) is added and the resultingmixture is heated on the steam bath for two hours. The filtered mixtureis made alkaline with 10% sodium hydroxide solution. Extraction withbenzene and evaporation of'the solvent in vacuo yields the product, 1,2dihydro 3 dimethylamino-4-methoxy-3H-pyrido- [3,2,1-kllphenothiazine.

A solution of 1.0 g. of the free base in 100ml. of ether is treated withan excess of alcoholic hydrogen chloride to produce the crystallinehydrochloride.

Example 25 S-methoxyphenothiazine (11.5 g.) is reacted with an excess ofacrylonitrile (500 ml.) together with 1 ml. of quaternary base solutionfollowing the isolation procedure of Example 14 to produce10-(2'-cyanoethyl)-3- methoxyphenothiazine which is then converted to 3-amino-1,2-dihydro--methoxy 3H-pyrido [3,2,1-kllphenothiazinehydrochloride using isolation and reaction conditions outlined inExample 1.

The cyano compound (12.0 g.) is hydrolyzed to the correspondingl0-(2'-carbomethoxyethyl) compound by reaction with 30.0 g. of hydrogenchloride in 150 ml. of dry methanol. Hydrolysis of this ester (6.0 g.)by refluxing in methanol with one equivalent of potassium hydroxideyields -(2'-carboxyethyl)-3-methoxyphenothiazine. A solution of 6.0 g.of this acid in 250 ml. of dry benzene is heated at reflux with 40 ml.of trifiuoroacetic anhydride for three hours. Washing with dilute sodiumhydroxide and evaporating the solution yields 2,3-dihydro-S-keto-S-methoxy 1H-pyrido[3,2,l-kl]pheno thiazine. The ketone(1.5 g.) is reacted with hydroxylamine hydrochloride (1.0 g.) to givethe corresponding oxime which is reacted with sodium amalgam (20.0 g.)and glacial acetic acid (1.5 ml.) in alcoholic solution to give3-amino-1,Z-dihydro-5-nrethoxy-3Hpyrido[3,2,1-kllphenothiazinehydrochloride. a

A mixture or" the hydrochloride (16.0 g.) in 400ml. of water is madealkaline with 10% aqueous sodium hydroxide solution. The tree amine isextracted with xylene.

The xylene extracts together with 15.0 g. of n-hexyl bromide and 12.0 g.of potassium carbonate are heated at reflux for ten hours. The cooledreaction mixture is poured into water and the xylene layerseparated.Upon evaporation of the solvent in vvacuo, 3-dihexylarnino-L2- 12dihydro-S-methoxy 3H pyrido[3,2,1-kllphenothiazine is obtained as a Waxymaterial.

Example 26 A' mixture of 16.0 g. of '3-amino1,2-dihydro-5-methoxy 3Hpyrido[3,2,l-kllphenothiazine hydrochloride (prepared as in Example 25)in 400 ml. of water is made alkaline with 10% sodium hydroxide solution,then acid with formic acid solution. Aqueous 37% formaldehyde ml.) isadded and the resulting mixture heated on the steam bath for two hours.The filtered mixture is made alkaline with 10% sodium hydroxidesolution. Extraction with xylene and evaporation of the solvent in vacuoyields 1,2-dihydro-3-dimethylamino-5-methoxy-3H-pyrido[3,2,1-kllphenothiazine which is purified by moleculardistillation at 190 and 10 microns.

A solution of the free base (1.0 g.) in ml. of ether is reacted with anexcess of alcoholic hydrogen bromide to yield the hydrobromide salt.

Example 27 Z-methyl-8-trifluoromethylphenothiazine (14.0 g.) is reactedwith an excess of acrylonitrile (500 ml.) under basic conditions andisolated as in Example 14 to produce10-(2'-cyanoethyl)-2-methyl-8-trifluoromethylphenothiazine.

The cyano compound (16.5 g.) is hydrolyzed to the corresponding10-(2'-carbomethoxyethyl) compound by reaction with a solution of 31.0g. of hydrogen chloride in ml. of dry methanol. Hydrolysis of this ester(6.0 g.) by refluxing in methanol with one equivalent of potassiumhydroxide yields10-(2-carboxyethyl)-2-methyl-8-trifluoromethylphenothiazine. A solutionof 7.5 g. of this acid in 300 ml. of dry benzene with 40 ml. oftrifluoroacetic anhydride is heated at reflux for three hours. Thesolution is evaporated after washing with dilute sodium hydroxide togive 2,3-dihydro-3-keto-4-methyl- 10-trifluoromethyl 1Hpyrido[3,2,l-kllphenothiazine. The ketone (2.5 g.) is reacted withhydroxylamine hydrochloride (1.3 g.) in boiling pyridine to give thecorresponding oxime which is then reacted with 23.0 g. of sodium amalgamin acidic alcoholic solution followed by isolation as in Example 1 togive 3-amino-1,2-dihydro- 4-methyl-l O-trifluoromethyl SH-pyrido [3,2,l-kl] phenothiazine hydrochloride.

A mixture of 18.6 g. of the hydrochloride in 300 ml. of water is madealkaline with 10% sodium hydroxide solution, then acid with formic acidsolution. Aqueous 37% formaldehyde (90 ml.) is added and the resultingmixture heated on the steam bath for two hours. The mixture is filteredand then made alkaline with 10% sodium hydroxide solution. Extractionwith benzene and concentration of the solvent yields the product,1,2-dihydro-3-dim-ethylamino-4-methyl-10-trifluoromethyl 3H-pyrido[3,2,l-kllphenothiazine.

The free base (2.0 g.) is dissolved in 200 ml. of ethyl acetate andtreated with excess maleic acid to yield the maleate salt.

Example 28 10-(2-cyanoethyl)-2-fluorophenothiazine is prepared byreacting 2-fluorophenothiazine (10.8 g.) with an excess of acrylonitrile(500 ml.) in the presence of a quaternary base (0.5 g.) as in Example14.

The solid cyano compound (15.0 g.) is hydrolyzed to the corresponding10-(2'-carbomethoxyethyl) compound by reaction with 31.0 g. of hydrogenchloride in 150 ml. of dry methanol. Hydrolysis ofvthis ester (7.0 g.)by refluxing in methanol with one equivalent of potassium hydroxideyields 10-(2'-carboxyethy1)-2-fluorophenothiazine. A solution of 6.0 g.of this acid in 250 ml. of dry benzene is heated at reflux with 40 ml.of trifluoroacetic anhydride for three. hours. Washing with dilutesodium hydroxide and evaporating the solution yields2,3-dihydrol0-fluoro-3-keto lH-pyrido[3,2,1-kllphenothiazine. The

ketone (2.0 g.) is reacted, by heating at reflux in 25 ml. of pyridine,with hydroxylamine hydrochloride (1.2 g.) to give the correspondingoxime which is then reacted with 23.0 g. of sodium amalgam and 1.5 ml.of glacial acetic acid in 90 ml. of ethanol and isolated as in Example 1to give 3-amino-1,2-dihydro-10-fluoro-3H-pyrido- [3,2,1-kl1phen0thiazinehydrochloride. I

A mixture of 13.6 g. of the hydrochloride in 300 m1. of water is madealkaline with sodium hydroxide solution, then acid with formic acidsolution. Aqueous 37% formaldehyde (90 ml.) is added and the resultingmixture heated on the steam bath for two hours. The filtered mixture ismade alkaline with 10% sodium hydroxide solution. Extraction withbenzene and evaporation of the solvent in vacuo yields1,2-dihydro-3-dimethylarnino-lO-fluoro 3H pyrido[3,2,1-kl]phenothiazine.

The product (1.0 g.) is dissolved in ether and treated with an excess ofalcoholic hydrogen chloride to separate the crystalline hydrochloride.

Example 29 2-bromophenothiazine (13.9 g.) is reacted with an excess ofacrylonitrile (500 ml.) and 1.5 ml. of 40% benzyltrimethylammoniumhydroxide solution as in Example 14 to produce10-(2'-cyanoethyl)-2-bromophenothiazine which is then reacted asdescribed in the following steps and isolated according to the methodsof Example 1 to produce 3-amino-10-bromo-1,2-dihydro-3H- pyrido[ 3,2,1kllphenothiazine hydrochloride.

The cyano compound (10.0 g.) is hydrolyzed to the corresponding10-(2'-carbomethoxyethyl) compound by reaction with 30.0 g. of hydrogenchloride in 150 ml. of dry methanol. Hydrolysis of this ester (7.0 g.)by refluxing in methanol with one equivalent of potassium hydroxideyields 2-bron1o-10-(2-carboxyethyl)-phenothiazine. A solution of thisacid (6.0 g.) in 250 ml. of dry benzene is heated at reflux with 40 ml.of trifluoroacetic anhydride for three hours. Washing with dilute sodiumhydroxide and evaporating the solution yields 10-bromo- 2,3 dihydro 3keto 1H pyrido[3,2,1 kllphenothiazine. The ketone (2.0 g.) is reactedwith hydroxylamine hydrochloride (1.2 g.) to give the correspondingoxime which is then reacted With 23.0 g. of sodium amalgam and 1.5 ml.of glacial acetic acid in 75 ml. of ethanol and is isolated as inExample 1 to give 3-amino- 10 bro-mo 1,2 dihydro 3H pyrido[3,2,1 kl]phenothiazine hydrochloride.

A mixture of 16.7 g. of the hydrochloride in 350 m1. of water is madealkaline with 10% sodium hydroxide solution, then acid with formic acidsolution. Aqueous 37% formaldehyde (90 ml.) is added and the resultingmixture heated on the steam bath for two hours. The filtered mixture ismade alkaline with 10% sodium hydroxide. Extraction with benzene andconcentration of the solvent yields the product: 10-bromo-1,2-dihydro-3-dimethylamino-3H-pyrido 3 ,2,1-kl] phenothiazine.

The product (1.0 g.) is dissolved in ether and treated with an excess ofalcoholic hydrogen chloride to separate the crystalline hydrochloride.

Example 30 10-(2'-cyanoethyl)-4-methylphenothiazine is prepared byreacting 4-methylphenothiazine (10.6 g.) with an excess of acrylonitrile(500 ml.) under basic conditions and isolated as in Example 14.

The cyano compound (5.0 g.) is hydrolyzed to the corresponding10(2-carbomethoxyethyl) compound by reaction with 15.0 g. of hydrogenchloride in 100 ml. of dry methanol. Hydrolysis of this ester (1.0 g.)by refiuxing in methanol with one equivalent of potassium hydroxideyields 10-(2'-ca.-rboxyethyl)-4-methylphenothiazine. A solution of 6.0g. of this acid in 250 ml. of dry benzene is heated at reflux for threehours with 40 ml. of trifluoroacetic anhydride. Washing with dilutesodium hydroxide and evaporating the solution yields 2,3-dihydro-3-keto-6-methyl-1H-pyrido[3,2,1kkllphenothiazine. This ketone (1.0 g.)is reacted in refluxing pyridine with hydroxylamine hydrochloride (0.6g.) to give the corresponding oxime. The oxime (1.2 g.) isreduced with20.0 g. of sodium amalgam in .100 ml. of acidic ethanol and isolated asin Example 1 to give 3-amino-1,2-dihydro-5-methyl-3H-pyrido[3,2,1-kllphenothiazine hydrochloride.

A mixture of 15.2 g. of the primary amine hydrochloride in 300 ml. ofWater is made alkaline with 10% sodium hydroxide solution, then acidwith formic acid solution. Aqueous 37% formaldehyde ml.) is added andthe resulting mixture heated on the steam bath for two hours. Thefiltered mixture is made alkaline with 10% sodium hydroxide solution.Extraction with xylene and evaporation of the solvent in vacuo yields1,2-dihydro 3 dimethylamino 6 methyl 3H pyrido [3,2,1-kllphenothiazinewhich is purified by molecular distillation at 200 C. and 10 microns.

A solution of 1.0 g. of the free base in m1. of acetone is reacted withan excess of citric acid in acetone to form the citrate.

What is claimed is:

1. A chemical compound of the class consisting of a free base and itsnontoxic, pharmaceutically acceptable, organic and inorganic, acidaddition salts, the free base having the structural formula:

N N-lower alkyl 3. A chemical compound having the fundamental structuralformula:

s ID N flower alkyl):

4. 3 amino 1,2 dihydro 3H pyrido[3,2,1 kl] phenothiazine.

5. 1,2 dihydro 3 dimethylamino 3H pyrido [3,2,1-kllphenothiazine.

6. 3 amino 1,2 dihydro 10 trifluoromethyl3H-pyrido[3,2,1-kllphenothiazine.

2,919,271 15 .16 7. 1,2 dihydro 3 dimethylamino 10 trifiuoro OTHERREFERENCES methyl-3H-pyrido[3,2,l-kflphenothiazine. C t 0 c 1 2 70941 J8. 10 chloro 1,2 dihydro 3 dimethy1amino B 1g em v0 pp um3H-pyrido[3,2,l-kllphenoth az n Mackie et ah: J. Chem. Soc., 1954, pp.25779.

' 5 Smith: J. Org. Chem, Vol. 15, pp. 1125-30 (1950). m the file thlsPatent Bykrit et aL: Ind. Eng. Chem, Vol. 42, p. 1864 1950 UNITED STATESPATENTS Fujii: JQ Pharm. Soc. Jap., vol. 77, No. 10, pp. 1068- 2,830,050Biel Apr. 8, 1958 1070 (October 1957).

2. A CHEMICAL COMPOUND HAVING THE FUNDAMENTAL STRUCTUAL FORMULA: